Strengthening the research and innovative
capacities of the Latvian Institute of Organic
Synthesis, the leading Baltic regional centre
for drug discovery: IOS today and strategic
plans of development
Ivars Kalvins , Coordinator
September 4, 2013
IOS – the leading innovator
in Baltic States
Esko Aho
R&D spending is actually transforming money
to knowledge and innovation is transforming
knowledge to money, but not only money but
well being and good human life as well
Latvian Institute of Organic Synthesis
(IOS)
• Latvian IOS was founded on the 2nd of
January, 1957 to perform pro-innovative
research in organic chemistry, molecular
biology and bioorganic chemistry.
• Currently, with 10 scientific
laboratories and 12 research groups
Latvian IOS is one of the leading
Professor S.A.Hiller
research centres of organic synthesis,
medicinal chemistry and drug discovery
in the Baltic region.
Both, independent and contract research projects are carried out in
cooperation with Latvian and foreign universities and pharmaceutical
companies.
Main Scientific Fields of Competence
• Organic synthesis
• Advanced technologies in organic synthesis
• Medicinal chemistry and drug discovery
• Molecular pharmacology
• Biological screening
• Analytical support
• Clinical trials
Identify disease
Isolate protein
involved in
disease (2-4yrs)
The Drug Discovery Process :
Lots of Time, Money & Risk
Find effective drug
against disease protein
(2-4 yrs)
Scale-up (2-3 yrs)
Preclinical testing
(1-3 yrs)
Human clinical trials
(2-5 yrs)
Formulation (1-3 yrs)
12 to 25 years
$400 - $800 M
FDA approval
(2-3 yrs)
IOS Resources
• 2424 m2 of well equipped laboratory space
• 109 highly qualified (PhD) chemists
• Specialists of molecular modeling
• Analytical support for qualitative and quantitative analysis
• Group of clinical trials
• 31 biologists and molecular pharmacologists
IOS Scientific Resources (Equipment)
IOS possesses all necessary equipment to perform research in drug
design and discovery
• NMR spectrometers (200MHz, 400MHz and 600MHz) with
various probes and accessories
•
Various spectroscopy equipment including EPR system, FTIR
spectrometer and X-ray diffractometer
•
Equipment for Gas Chromatography (FID, ECD, TCD, MSD),
High Performance Liquid Chromatography (UV, fluorescence
detection, MS/MS) and High Performance Thin Layer
Chromatography
•
Equipment for physical tests and pharmaceutical technical
procedures of finished dosage forms.
•
Equipment for pharmacological and biological studies
•
Automated
synthesis
microwave
synthesizer
for
high
throughput
IOS Scientific Resources (Equipment)
LC-MS-MS
GC-MS
GC and HPLC as a Routine
IOS scientific research
•The institute publishes about 120 scientific
papers annually, in average 3 PhD works are
made every year.
• 4 monographs, 20 brochures, 464 scientific papers and 406
proceedings were published by scientists of IOS during last 5
years.
• IOS is participating in in a number of collaborative
projects with universities in Sweden, France, Greece and
other countries, as well as in Visby Network grants with
Uppsala University, Sweden, 3 NATO projects, 6 COST
projects etc.
IOS Scientific Journals
• IOS is an editor of widely recognized journal
”Chemistry of Heterocyclic Compounds”, published both
in Russian (by IOS) and English (by Springer).
IOS pro-inovative research
• IOS discovered 17 original medicines and 86
original manufacturing processes of Active
Pharmaceutical Ingredients (API).
• 3 original medicins are under clinical trials
worldwide now.
IOS Contract Research
• International cooperation in drug design and discovery
by IOS was started already before collapse of the USSR.
Nowadays IOS has ongoing projects with 11
pharmaceutical companies worldwide. There are very
many different cooperation models – starting from simple
contract research projects and up to close partnership
during the whole process of drug design and discovery.
• The most important industry partners of IOS come
from UK, Germany, Denmark, Sweden, Finland, USA,
Japan and Latvia.
• As a result, in collaboration with business partners, in
the last 5 years 64 new patents have been filed.
Protected Inventions of IOS scientists
•
•
•
•
•
•
•
•
•
•
•
•
•
•
US patents
39
US patent applications
43
EPO patents
29
EPO patent applications
43
WIPO patent applications
85
Euro-asian patents
19
Japanese patents and applications
38
Ukraine patents
11
Russia patents un author sertificates
45
Latvian patents
57
Patents and applications in total
406
Not published patents
34
Non-identical patents in total (01.02.2013)
440
Patent families consists of 1000 patents un patent applications
Protected Inventions of IOS scientists
100
99
96
80
85
80
71
60
51
40
20
0
46
27
2004
2005
2006
2007
2008
2009
2010
2011
Patent Protected
Intellectual Property of IOS
Four levels of cooperation are typical
for IOS contract research
• Synthesis of known compounds and building blocks
(low interest for IOS),
• Development of methods for synthesis of leading
compounds,
• Structure optimization for leading compounds (hit to
lead),
• Discovery of structures with high binding potential
(hits) with further search for leading compounds and
clinical candidates (primary screening on binding assays
also is possible).
Income, thsd. EUR
Structure of IOS budget
14 000
12 000
10 000
8 000
6 000
4 000
2 000
2007
2008
2009
2010
2011
Contract research Grants, including joint projects with industry
2012
Income sources for wages in IOS (2012)
Valsts
State finansējums
budget
12%
ERAF/ESF
42%
7th Eiropas
Framework
Citi
projekti
(7.ietvars)
45%
1%
Komerclīgumi
Contract
research
Achievements of the IOS Contract Research
The latest and most important achievements of the contract
research at IOS are as follows:
• IOS participated in the development of the first antiAlzheimer disease medication, registered both in the
USA and EU. Both chemical development and clinical
trials were performed by the experts of IOS. Estimated
turnover of this medicine is 2.0 billion USD annually.
• Together with a German company IOS has developed a
new medication for tinitus, which is currently
undergoing clinical Phase III trials in Japan. Scientists
from IOS were involved in design of the active entity
and synthetic development of the molecule.
4/7/2015
Achievements of the IOS Contract Research
• In co-operation with partners in the UK and Denmark a new anti
cancer drug Belinostat has been discovered (EP 2292593 A2, HDAC
inhibitor, under clinical trials in the USA and the EU)
• Belinostat is currently udergoing last Phase clinical trials for various
cancer types in USA and Europe: Peripheral T-Cell Lymphoma
(PTCL), for cancer of unknown primary (CUP).
• Additionally, the National Cancer Institute (USA) is currently
conducting several clinical trials of Belinostat in a variety of
haematological and solid tumours.
• US company Spectrum licensed the rights to Belinostat for North
America and India, and an option for China, in exchange for an
upfront cash payment of $30 million, potential milestone payments of
up to $320 million, and one million shares of Spectrum common, as
well as double-digit royalties on net sales of Belinostat ( it is estimated
as a billion deal)
Achievements of the IOS Contract Research
• In collaboration with a Swedish pharmaceutical company
new clinical candidates for a new type anti-inflammatory
medicine were discovered (EP 1 778 632 B1) (selective and
new type of prostaglandin E synthase inhibitors)
•In connection with the collaboration and licensing
agreement, our customer received a payment and the
company is also entitled to compensation for development
work, as well as milestones when certain set targets are
attained. The total payments may amount to EUR 250m,
excluding royalties.
4/7/2015
IOS contribution to the development of
Latvian pharmaceutical industry
• Export value of IOS original medicines Mildronate
and Ftorafur from Latvia exceeded 100 Mio EUR
• Mildronate is Latvian bestseller among high-tech
products
• IOS pro-inovative research support
competetiveness and growth of “Grindex”,
“Olainfarm” and other Latvian pharmaceutical
companies
• IOS improved meldonium, phenotropil, phenibut,
and other new molecules – a waranty of Latvian
pharmaceutical industry sustainability!
Success story of IOS pro-innovative research in
cardiology
Grindex funding
2013. - subacute and chronic
toxicity investigations done
2012. - final dosage form developed,
acute toxicity tests done
(2010- 2013), ERAF funding Grindex and IOS co-funding
2012.- WO patent application
for new clases of compounds
Grindex funding
2010. - US patent application for
first class of active compounds
(2005-2009) State research
program funding
2009.– new cardioprotective drug
candidate discovered (substantially
improoved mildronate analog)
2006. – screening system developed for
testing meldonium–like cardioprotective
compounds
Achievements of drug candidate research in IOS
• Original anticancer compound with excelent
efficacy against human pancreas tumour’s
xenografts
•Clopidogrel analog with improved efficacy
• Amlodipine analogs with improved
pharmacological properties
• Cognitive functions enhancing molecule (50-times
more active as piracetam)
3 steps to success
Basic knowledge
and starting
materials
Product
(commercially
available)
Developing new
product or process
R&D
1. Technology
development
Small scale
production
Scale up
Knowledge
Transformation into
commercially available products
2. Technology transfer
& deployment
3.
Stimulating
3. Simulation
market demand
market
demand
Addopted from http://ec.europa.eu/enterprise/sectors/ict/key_technologies/kets_high_level_group_en.htm
What is the nishe for pharmaceutical
innovation in Baltic countries?
• Creation of patentable technologies for API of generic
drugs in form of GMP class of drug master file
• Discovery of new drugs
• Development of new drugs: discovery of active
ingredients and methods of its manufacturing,
creation of galenic formulation and analytics, GLPclass preclinical and clinical testing, experimental
GMP production of generics and original drugs
Therefore specific infrastructure for drug discovery,
development and experimental production is needed
in Baltic’s!
Clustering of Drug Discovery and Development
activities in Latvia (BioPpharmAlliance)
Search of Biochemistry
targets
and
all partners screening
BPhC, LU
Target
Structural biology
and modeling
IOS, BMC
Organic and
Medicinal
Chemistry
RTU, OSI
Compounds
Drug candidate
Pilot
production
To clinical trials
GLP Toxicology
BPhC
Pharmacology
BFC, IOS, LU
Pharmacodynamics and
metabolism
BPhC, OSI, LU
Research Commercialization: public finance
Scientific
Marketed
leverages
private
Discovery
product
IPO
Low
Lab Model
IP protection
Technology
Development
Phase
A Round
First Customers
Prototype
Create Business
Mgt Team
Market
Assessment
Business
Models
Business
Building
Phase
Probability of Success
Probability of Success
B Round
Manufacturing
Model
Commercialization Progression
Low
Bio Pharm Alliance partners in Latvia
 Institute of Organic Synthesis (IOS),
 Scientific Institute of Food Safety, Animal Health and
Environment (BIOR),
 Study Centre of Biomedicine (BMC),
 University of Latvia (LU),
 Riga Technical University (RTU),
 Daugavpils University (DU),
 Pauls Stradins Clinical University Hospital,
 Eastern Clinical University Hospital,
 Mechanics and Technology College of Olaine
 Chemical, pharmaceutical and biotechnological companies
Infrastructure of BioPharmAlliance
 Pharmacology and molecular biology research centre including
GLP-compliant test and animal facility and National Biobank
(participation in EU-OPENSCREEN, EATRIS);
 Scale-up and pilot production facilities of chemistry and
biotechnology based products, vaccines, personalized medicine
products and final dosage forms of both human and veterinary
medicines (participation in EATRIS);
 Centre of stuctural biology on the basis of existing competence
in protein crystallography and NMR studies (participation in
INSTRUCT)
INNOVABALT – STAIRWAY TO
EXELENCE IN DRUG DISCOVERY!
Let us do it together!
Thank you for attention!